This article provides a comprehensive review of the current literature and summarizes the experience of the German cooperative protocols for nontesticular germ cell tumors (MAKEI) on the use of alpha 1-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) for diagnostic evaluation in pediatric oncology. Based on this evaluation, this review proposes guidelines for the initial diagnostic work-up for children with clinically suspected secreting tumors. AFP and beta-hCG represent the characteristic tumor markers of malignant epithelial liver tumors and malignant germ cell tumors (GCT). They play an important role in the initial diagnostic evaluation as well as in the follow-up examination during therapy. Current therapeutic strategies for both tumor types include preoperative chemotherapy followed by delayed tumor resection. Therefore, it is essential for the pediatrician in charge to be aware of the broad differential diagnosis of elevated AFP and beta-hCG. In a well-defined clinical setting, these tumor markers allow clinical diagnosis without histological confirmation, but the physiologically elevated AFP serum levels in infancy or unrecognized benign conditions, such as hepatic diseases or hereditary disorders, must also be considered as differential diagnoses. Therefore, the laboratory investigations should include liver parameters in all patients to exclude hepatic disease. In addition, pregnancy must be excluded in adolescents. Careful history taking and clinical examination will further help to rule out metabolic disorders or ataxia teleangiectasia that are associated with elevated AFP levels. Having excluded these conditions, elevated AFP levels above the age-related normal range (with or without high beta-hCG), indicate malignant epithelial liver tumors in primary liver lesions. At virtually all other sites, the diagnosis of a malignant GCT with a substantial yolk sac tumor and/or choriocarcinoma component can be established. Pancreaticoblastoma should be considered in the differential diagnosis of tumors of the upper abdomen, and biopsy must be performed. Other childhood tumors are rarely associated with AFP or beta-hCG production, usually at only moderately elevated serum levels, and in most patients these tumors can be excluded by clinical and radiological examination.